OBJECTIVES To measure health-related quality of life (HRQoL) by SF-12 in multiple sclerosis (MS) patients and to compare the SF-12 component scores in MS patients with available US national average scores (norm). METHODS ROBUST is an ongoing multi-center prospective US observational study among MS patients, involving a series of questionnaires completed via a web tool. A battery of items in the patient questionnaire is the SF-12 (Version 2). The ROBUST baseline SF-12 Physical Component Summary (PCS-12) and Mental Component Summary (MCS-12) scores were analyzed against US population norms. RESULTS A total of 191 ROBUST participants completed baseline HRQoL assessments and were included in this analysis. The mean (SD) age was 40.6 (11.2) years and a majority were female (81.2%), white (86.9%), married (68.6%) and worked full- or part-time (61.2%). The MCS-12 showed a gradual increase with the level of education. Among the ROBUST population, the mean (SD) scores on PCS-12 [40.64 (11.18)] and MCS-12 [42.54 (11.44)] were significantly lower than the norm [PCS-12 norm: 49.63 (p<0.0001); MCS-12 norm: 49.37 (p<0.0001)]. The PCS-12 [40.11 (11.17)] and MCS-12 [42.42 (11.44)] scores for female MS patients and the PCS-12 [42.92 (11.08)] and MCS-12 [43.05 (11.55)] scores for male MS patients were also significantly lower than the respective norms [all p<0.0001]. Similarly, SF-12 scores for MS patients by age groups [18-24 years; 25-34 years; 35-44 years; 45-54 years; 55-64 years] were significantly lower compared to norms for corresponding age groups [all p<0.001]. Among these age groups within the ROBUST population: PCS-12 scores were lower after 40 years compared to that in younger age group, while MCS-12 scores do not show this same change with age. CONCLUSIONS SF-12 component scores were significantly reduced in the ROBUST population compared to the available national average scores, suggesting a lowering of general HRQoL in MS population.